The molecular mechanisms and genetic pathways involved in human aging and associated organ degeneration are not well understood. Human aging is associated with functional defects in many highly proliferative tissues. These tissues must be continuously replenished by tissue stem cells, since differentiated cells are lost throughout life. Increasing evidence suggests that the normal human aging process is associated with a decline in stem cell function. Therefore, to devise approaches to help ameliorate the pathological effects of the normal aging process, a greater understanding of how stem cell functions are altered during human aging is required. Studies using mouse models and human cell lines point to the maintenance of telomere homeostasis as critical for stem cell function. Telomeres are nucleoprotein structures that play essential roles in maintaining chromosome integrity and genome stability. In mammals, telomeres consist of TTAGGG repetitive sequences and are maintained by the enzyme telomerase. Telomerase is limiting in human somatic cells, resulting in progressive telomere shortening. Dysfunctional telomeres that can no longer exert end-protective functions are recognized as DNA double stranded breaks by the DNA damage repair (DDR) pathway. While telomere repeats are used by eukaryotes to solve the end replication problem and confers chromosome end protective functions, they pose a unique problem during DNA replication since they resemble fragile sites. This proposal addresses a largely unexplored area of telomere biology-what impact does proper telomere replication play in the maintenance of genome stability and cellular homeostasis? Our proposal is innovative because it addresses the hypothesis that failure to properly replicate telomeres may be as important as telomerase deficiency to generate an unstable genome.